DESCRIPTION (Applicant's abstract): The goal of the proposed project is to develop a nonaddicting analgesic for chronic and acute pain. There is an urgent need for effective treatments for chronic, neuropathic pain, a relatively common complication of diabetes. As diabetic neuropathy progresses, neuropathic pain becomes increasingly difficult to treat with currently available analgesics such as anti- depressants and opioids. Morphine and its analogs are routinely prescribed, inspite of their side effects, because good analgesics are currently not available. Newly identified nociceptin and its analgesic activity in animal studies provides a potential target for relief of chronic and neuropathic pain. Because the nociceptin antagonist does not act through opiate receptor, addiction and opioid-related side effects may not be a problem. However, because of its size (17 amino acid) and peptidic nature nociceptin, is not going to make it as a therapeutic agent; a small non-peptide analog will be required to commercialize any compound. We propose to use a receptor-based, multidisciplinary approach for drug design, which consists of computer modeling, chemical synthesis, and biological evaluation. The specific aims for Phase I feasibility studies are: i) to conduct computer modeling experiments to design small modified peptide analogs of nociceptin with high binding affinity and functional activity. This will involve appropriate amino acid substitutions. Our model for the receptor-bound conformation of nociceptin will form the basis for designing these analogs. ii) Once a small potent peptide is identified it will be used as a template for designing a non-peptide analog. iii) New analogs will be evaluated for binding affinity and functional activity. Phase II project will involve refinement of potent peptide identified in Phase I. All possible modifications will be tried. Various strategies for delivery system to facilitate crossing the blood-brain-barrier will be developed. Animal studies will be conducted to study analgesic activity. IND will be filed on the most active compound and marketing will be conducted. The data generated by these studies will provide important information to bring this technology to a level of maturity where it can complete successfully for commercial funding to bring an effective therapeutic agent to clinical use. PROPOSED COMMERCIAL APPLICATION: Non-peptide analogs of nociceptin, prepared under this program, will be developed into therapeutics that can be used for the treatment of chronic and neuropathic pain. For this type of debilitating chronic injury, there is no suitable treatment available currently. Market opportunity for analgesics is worth in excess of $5 billion and is growing rapidly. The development of non-peptide agonists would likely add effective compounds for this enormous market.